1. Field of the Invention
The present invention relates to a composition for the sustained delivery of a hydrophobic drug and to a process for preparing the same. More specifically, the present invention relates to a liquid composition for the sustained delivery of a hydrophobic drug comprising: i) an amphiphilic diblock copolymer; ii) a hydrophobic drug; iii) a biodegradable polymer; and iv) liquid polyethylene glycol or derivatives thereof. The amphiphilic diblock copolymer forms polymeric micelles in the liquid polyethylene glycol and the hydrophobic drug is physically trapped within the micelles. Furthermore, the biodegradable polymer forms matrices in the liquid polyethylene glycol such that the drug containing micelles in the polyethylene glycol are contained within the biodegradable polymer matrices. When injected into a living body, the composition forms a polymeric implant comprising the drug containing micelles within the polymeric matrices. The micelles and drug are gradually released from the matrices and the drug is then slowly released from the micelles in a controlled manner providing for a constant drug concentration in vivo for an extended period of time.
2. Related Art
Numerous studies regarding drug delivery systems have been conducted with a variety of drugs and methods in an effort to maximize the efficacy and effects of drugs and minimize the side effects of drugs by efficient administration means and controlling the rate of drug release.
Biocompatible, biodegradable polymers have been widely used in the medical field as surgical sutures, tissue regenerative induction membranes, protective membranes for the treatment of wounds, and drug delivery systems. Among biodegradable polymers, polylactide (PLA), polyglycolide (PGA) and a copolymer (PLGA) of lactide and glycolide, are all commercially available. They have good biocompatibility and are decomposable in the body to harmless materials such as carbon dioxide, water, etc.
One example of a biodegradable polymeric drug delivery system is a system wherein a drug is contained in a biodegradable polymer matrix. These systems have the disadvantage of having to be surgically implanted. In the form of injectable drug delivery systems, polymeric microspheres and nanospheres are known in the art. However, those systems have disadvantages in that they require special preparation methods. In addition, since the biodegradable polymers used can only be dissolved in organic solvents, preparation requires the use of organic solvents harmful to the human body and therefore any residual solvent remaining after preparation of the microspheres must be completely removed. Furthermore, some drugs, such as polypeptides and proteins, may lose their physiological activity after contacting organic solvents.
Most drugs, after administration, must have a constant plasma concentration in order to provide for the desired pharmacological effects. In particular, drugs with short half-lives must be administered frequently to achieve effective plasma concentrations. For such drugs, sustained delivery formulations from which the drugs are slowly released to continuously provide their pharmacological effects, have been developed.
Many important drugs are hydrophobic and have limited solubility in water. In order to attain the expected therapeutic effect from such drugs it is usually required that a solubilized form of the drug be administered to a patient. Therefore, solubilization of a poorly water soluble drug is key technology in the preparation of a formulation for oral or parenteral, especially intravenous, administration of the drug. Common methods used for solubilization of poorly water soluble drugs are: i) dissolving the drug in a co-solvent of a water-miscible organic solvent and water; ii) modifying the drug to its salt form which is soluble in water; iii) forming a soluble drug-complex using a complexing agent; iv) introducing a hydrophilic group into the drug molecule; v) micellizing the drug in an aqueous medium with a surfactant, and vi) dispersing the drug in water to form emulsions, liposomes, nanoparticles and the like [S. Sweetana, et al., Solubility Principles and Practices for Parenteral Drug Dosage Form Development, PDA J. Pharm. Sci. & Tech. 60 (1996) 330–342].
U.S. Pat. No. 5,543,158 discloses a nanoparticle, wherein a drug is entrapped therein, formed of a block copolymer consisting of a hydrophilic polyethylene glycol block and a hydrophobic poly(lactide-co-glycolide) block. The nanoparticle has a hydrophilic outer shell that can decrease uptake of the drug by the reticuloendothelial system thus allowing it to remain in the systemic circulation for an extended period of time. However, in order to manufacture the formulation, organic solvents harmful to the human body have to be used in order to dissolve the drugs and the polymers. Furthermore, the drugs are completely exhausted from the blood within several days because they are intravascularly injected.
X. Zhang et al. reported that a polymeric micelle prepared with a diblock copolymer of poly(lactic acid) and monomethoxy poly(ethylene glycol) was useful as a carrier of paclitaxel [X. Zhang et al., Int. J. Pharm. 132 (1996) 195–206], and Shin et al. disclose a solubilization method for indomethacin using a diblock copolymer of poly(ethylene glycol) and polycaprolactone [I. Gyun Shin et al., J. Contr. Rel. 51 (1998) 13–22]. In these methods, a poorly water soluble drug is incorporated in a polymeric micelle, wherein the polymers are biocompatible and biodegradable. According to their methods, a drug and a block copolymer are dissolved together in an organic solvent, especially in a water-miscible organic solvent such as tetrahydrofuran or dimethyl formamide. The polymeric micelles are prepared by dialyzing the solution in water first and then freeze-drying the aqueous micellar solution. Alternatively, a solution of a polymer and drug in a water-miscible organic solvent, acetonitrile, is prepared. The organic solvent is slowly evaporated to give a homogeneous drug-polymer matrix and the matrix is then dispersed in an aqueous medium at ca. 60° C. to form the polymeric micelles.
Implants can be directly applied to a particular body site rather than being intravascularly injected. For example, U.S. Pat. No. 5,869,079 discloses an implant comprising the poorly water-soluble drug dexamethasone, a copolymer of lactic acid and glycolic acid, and hydroxypropyl methylcellulose. In addition, U.S. Pat. No. 6,004,573 discloses that a PLGA-PEG-PLGA triblock copolymer made up of hydrophobic poly(lactide-co-glycolide) (PLGA) blocks and a hydrophilic polyethylene glycol (PEG) block can be used as an implant for effectively delivering poorly water-soluble drugs. However, the above formulations fail to provide for effective plasma concentrations of poorly water-soluble drugs due to their extremely low solubility in body fluids. Thus, a composition for use as an implant that can be prepared by a simple procedure, and which releases the hydrophobic drug over an extended period of time and which is administered by a single injection and then decomposes into materials harmless to human body, is needed.